#2021BSQ-NOV Q31
These are more clearly seen in type I DM.
In type 2 DM, vascular and tubulointerstitial changes predominate.

1. changes in glomerular hemodynamics
   1. DM -> somehow ↑ RAAS activity -> increased GFR -> In early stages of DM: Glomerular hyperfiltration.
   2. Glomerular HYPERFILTRATION is a recognized phenomenon in early diabetes.
   3. Hyperfiltration is associated with increased risk of progression of kidney function decline.
   4. Also, renal autoregulation of blood flow may be impaired - exposing the kidney to effects of hypertension. => increased GFR
2. Oxidative stress and inlammation
   1. DM -> Advanced Glycation End products (AGE) -> inflammation
3. Interstitial fibrosis and tubular atrophy.
   1. DM -> Hyperglycaemia -> ↑ activity of hexosamine pathway +↑ RAAS acvitity -> ↑ TGF-Beta production -> fibrosis and atrophy

Glomerular changes

Mesangial proliferation -> further proliferation + matrix deposition -> PAS positive kimmelstiel-Wilson bodies.

1. Diffuse basement membrane thickening along it's entire length
2. Diffuse mesangial sclerosis <- diffuse increase of mesangial cells and matrix.
3. Nodular glomerular sclerosis <- a pattern of sclerosis with nodules of matrix at the periphery of the glomerulus. AKA Kimmelstiel Wilson nodules. <- Pathognomonic of DM (almost)
   These changes are present in all patients with renal impairment in T1 DM.

Chronological sequence of changes

1. Glomerular basement membrane thickening is the first to be seen.
2. Thickening of the tubular basement membrane parallels GBM thickening.
3. Mesangial proliferation and sclerosis is seen later.

[!INFO]
This 'neat' sequence is best observed in type 1 DM. It's more complicated in Type 2

Non glomerular changes

• Efferent and afferent arteriolar hyalinosis - Deposition of plasma proteins (complement, immunoglobulins and fibrinogen) replace the smooth muscle cells of arteriole.

[!INFO]

Glomerulus from a type 1 diabetic (T1DM) patient with diffuse (long thick arrow) and nodular (short thick arrow) mesangial expansion and afferent (double thin arrows) and efferent (single thin arrow) arteriolar hyalinosis. Source

Hypothalamus

Is a bilateral collection of nuelcei divided into three zones surrounding the third ventricle and the mammillary bodies.

Gross anatomy


Micro anatomy

Hypopituitarism

[!info] ACTH and TSH are the "hardiest" trophic hormones
Organic pituitary disease affects GH AND GONADOROPHINS >> ACTH AND TSH.
ACTH and TSH are the "hardiest" trophic hormones.
The "G" hormones are more sensitive

Causes of hypopituitarism

[!info] Hypothalamic Vs. Pituitary causes
Pituitary lesions won't reduce ADH secretion but hypothalamic lesions will reduce ADH secretion


Growth hormone

Growth Hormone Physiology

[[2021-Basic Sciences#Glucose regulating hormones|IGF]] <<- Action of IGF

[[Encodrinology MCQ discussion#Growth Hormone disorder diagnosis and investigation]]

Stimulation: GHRH, Ghrelin
Inhibition : Somatostatin

Pattern of secretion:
GH secretion peaks in early puberty
Then gradually decreases.

[!TIP] IGF Vs. GH Vs. Insulin
Despite GH having anti-insulin effects, IGF-1 has insulin like activity

Factors increasing GH secretion

• Peak GH secretory activity occurs within an hour after the onset of deep sleep.
• Exercise
• trauma and sepsis (it's a stress hormone)

Actions of GH

[!Tip] Mnemonic: GH affects all macromolecules - makes things grow

• Lipids -> increase lipolysis
• Proteins -> Increased protein synthesis
• Glucose -> Promotes insulin resistance
• Electrolytes -> Phosphate, salt and water retention
• Bone -> Epiphyseal bone growth

Causes of GH abnormalities

Reduced secretion

In adults, causes are the same as causes of [[Hormone Physiology#Hypopituitarism|hypopituitarism]].
In children, GH deficiency can be caused by various inherited causes as well. (Acquired causes are same as in adults)

Increased secretion

Commonest cause in adults: somatotroph adenoma

Commonest causes in children: Early childhood GH excess is usually due to GHRH excess. (i.e usually not a tumour). They will present with gigantism (or tall stature)

Causes of Increased GH presenting as gigantism (i.e ↑ GH before epiphyseal fusion)
+ Most commonly due to isolated GH excess
+ Could also be due to
+ McCune-albright syndrome - diagnosed in young adults
+ Carney complex - presents in middle aged people
+ MEN 1 and MEN 4 (4th to 5th decates of life)
+ Neurofibromatosis
+ Famlilial isolated pituitar adenomas - autosomal dominant #autosomalDominant

[[Encodrinology MCQ discussion#Growth Hormone disorder diagnosis and investigation|Diagnosis and Investigation of GH disorders]]

Acromegaly

Associated features and pathologic basis

As commonest cause is somatotroph adenoma:
acreomegaly is associated with symptoms caused by pressure effect of adenoma:

1. Headache, bitemporal hemianopia, cranial nerve defects
2. Decreased secretion of other pituitary hormones -> most commonly gonadotrophins
   1. Menstrual dysfunction, vaginal atrophy, galactrorrhea
3. Hyperprolactinaemia - either increased [[#Prolactin]] secretion from the somatotroph adenoma or inhbition of dopaminergic inhibition
4. Effects of GH and IGF-1 Excess:
   1. Soft tissue overgrowth - large tongue, carpal tunnel syndrome + the other classic ones
   2. Joints - Hypertrophic arthorpathy, back pain, kyphosis, hypogonadism induced osteoporosis
   3. Visceral organ enlargement - thyroid, heart, liver, lungs
      1. heart: cardiomyopathy and LVH with diastolic dysfunction and arrhythmias - secondary to hypertension
      2. Hypertension: GH-IGF-I excess -> enhanced sodium- and water retention -> expansion of plasma volume and increased systemic vascular resistance. Source
         3. Hyperinsulinaemia may also stimulate salt and water retention Source
   4. Metabolic - insulin resistance and DM
   5. Sleep apnea
   6. colonic neoplasms

Calcium disorders

[!Info] Hypercalcemia is MUCH more common than hypocalcemia
Usually due to primary hyperparathyroidism; occurs in older females
primary hyperparathyroidism and malignancies = 90% of cases

^da9653

[!WARNING] Hypercalcaemia >>> hypocalcaemia
Hypercalcaemia is much more common than hypocalcaemia

Calcium regulation

Vitamin D

Activated vitamin D (1,25 dihydroxyvitami D) regulated gene transcription by binding to intracellular receptors.

• Its most important biological action is to promote enterocyte differentiation and the intestinal absorption of calcium.
• Other effects include
  • a lesser stimulation of intestinal phosphate absorption
  • direct suppression of parathyroid hormone (PTH) release from the parathyroid gland,
  • regulation of osteoblast function, and
  • permissively allowing PTH-induced osteoclast activation and bone resorption.
    • Illustrative point: "in the elderly, low vitamin D and secondary hyperperparathyroidism reduced bone mineral density" - Kumar & Clark.

^83ab8b

The renal 1-alpha-hydroxylase enzyme which activates vitamin D is primarily regulated by the following factors:

• PTH
• Serum calcium and phosphate concentrations
• Fibroblast growth factor 23 (FGF23)

Activated vitamin D levels are elevated in #pregnancy

The main reason for hypocalcemia in CKD is the impaired activation of vitamin D.

Parathyroid hormone

^0f3395

Functions of Parathyroid hormone

PTH increases renal phosphate excretion and increases plasma calcium by:

• increasing osteoclastic activity in bone (a rapid response)
• increasing intestinal absorption of calcium (a slowerresponse)
• increasing 1α-­hydroxylation of vitamin D (the rate-­limiting step)
• increasing renal tubular reabsorption of calcium.

Parathyroid hormone secretion is directly inhibited by high calcium levels.
This happens through binding of calcium to a GPCR on the parathyroid cells called CaR.

[!INFO] Familial hypo and hypercalcemia
Loss of function mutations of CaR cause chronically elevated Calium levels. (Familial hypocalciuric hypercalcemia. (i.e normal to elevated PTH)
Gain of function mutations of CaR cause familiar hypercalciuric hypocalcemia. (?supressed PTH)

Magnesium is needed for the action of PTH. Hypomagnesaemia impairs PTH release and impairs peripheral organ sensitivity to PTH.

PTH level increases with age, possibly due to declining renal function -> reduced activated Vit D level, declining oestrogen levels and / or declining calcium absorption. Source

Calcitonin

#2021BSQ-NOV Q08

• Produced by parafollicular C cells of the thyroid;
• Despite medullary thyroid CA patients having very high calcitonin levels, their calcium levels are not abnormal.
• Effect: It inhibits osteoclastic bone resorption and increases urinary calcium excretion.
• Calcitonin is elevated in Zollinger-Ellison syndrome and in Pernicious anaemia.
• Calcitonin half life is only 10 minutes.
• Not an important hormone in normal physiology.
• Unlike Vitamin D and PTH, calcitonin is not involved in phosphate homeostasis.
• May be important in pregnancy because it protects the mother's bone against reabsorption when producing milk and providing calcium for foetal bones.

Indications for therapeutic used:

• postmenopausal osteoporosis
• Paget's disease of bone
• Hypercalcemia

Renal handling of calcium

^070bf7

About half of total calcium is protein unbound. The remainder ('complexed' to citrate and phosphate and 'unbound') making up the other half is the 'filtrable' part.
Almost all the filtered calcium is reabsorbed.

PTH and activated vitamin D promote calcium re-absorption in all areas except the PCT. (DCT, TAL, Connecting tubules)
Source

PTH and activated vitamin D promote expression of calcium transport proteins in these regions.
Source ^84acf2

Hypercalcaemia

[[Encodrinology MCQ discussion#Q 10: Hypercalcemia|MCQ discussion]]

Causes are devided into

• paratyroid hormone dependent causes
• parathyroid hormone independent causes
  This is how we should think about each condition below.

malignancy and primary hyperparathyroidism = 90% of cases.

• Primary hyperparathyroidism is the commonest cause of hypercalcaemia by far
  • Ix - Patient has Elevated PTH, Elevated Ca2+ and low PO4 and is asymptomatic. No need for further evaluation
• malignancies including myeloma


Causes of Severe hypercalcaemia :

• malignant disease - One of the causes of symptomatic hypercalcaemia.
• hyperparathyroidism
• chronic kidney disease
• vitamin D therapy.

Investigations for hypercalcaemia

• Serum PTH, Phosphate, Calcium
• 23 h urinary calcium OR single calcium : creatinine ratio. (Do in young patient with moderate incraese in Ca2 level -? familial hypocalciuric hypercalcaemia. (FHH))
  • The CaSR is a member of G protein-coupled receptors and suppresses PTH secretion by sensing high plasma Ca2+ level in the parathyroid glands). In the kidney, the CaSR is most highly expressed in the TAL. Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant disease due to the mutation of CaSR gene, and is manifested as hypercalcemia, hypophosphatemia, parathyroid hyperplasia, and unusually low renal clearance of calcium.Source
• Increased Serum ALP
  • Elevated in severe parathyroid bone disease (i.e PTH is high)
  • but if not (PTH is low) , suggests alternative cause.

Types of Hyperparathyroidism

Primary hyperparathyroidism

• Single adenoma 80%
• Diffuse gland hyperplasia (20%)
• parathyroid carcinoma is rare - causes intractable hypercalcemia
• hyperparathyroidism-jaw tumour syndrome

Secondary hyperparathyroidism

Physiological compensatory mechanism for hypocalcemia.
Therefore, ↑ PTH levels, but normal calcium level.

Tertiary hyperparathyroidism

After chronic secondary hyperparathyroidism, gland becomes autonomous.
↑Ca2+ and ↑↑ Phosphate

Hypocalcaemia

Not very common

Hypoparathyroidism

In hypoparathyroidism, there is increased bone minieral density. But the bone is not properly formed.
So there are increased fractures

Pseudohypoparathyroidism

Caused by a defect in PTH receptor
Biochemical manifestations are just like hypoparathyroidism (Low Ca2+ and high Phosphate)
BUT having HIGH PTH level
Patients have albright phenotype

Pseudo-pseudo hypoparathyroidism

Patients have albright phenotype BUT
All biochemistry is normal

Phosphate and calcium

[!NOTE] What is the relationship between Calcium and Phosphate?
Calcium phosphate is insoluble and Ca and PO4 can remain in solution so long as the solubility product is not exceeded.
In patients with hyperphosphataemia, there is indeed deposition of calcium phosphate. (familiar tumoural calcinosis)
So it makes sense that as a physiological mechamism, PTH increases calcium level and simultaneously decreases phosphate level. to prevent CaPO4 deposition

To illustrate this further:
"The ensuing hyperphosphatemia may induce potentially symptomatic hypocalcemia due to calcium-phosphate precipitation in the tissues." - Source: Hyperphosphatemia

Phosphate physiology

• Directly related to calcium metabolism
• Main storage is bone
• tiny bit in serum
• reabsorption exclusively in the PCT - active process.
  • Reabsorption is reduced by PTH; ∴ ⬆ PTH → ↓Phosphate
  • Osteoblast secreted phosphaturic factors (eg. FGF23- the most studied one) causes ↑ urinary phosphate excretion
  • FGF23 is the earliest marker of abnormal phosphate handling in CKD
  • Inherited defect of FGF23 --> hyperphosphataemia -> familiar tumoural calcinosis

Prolonged hyperphosphataemia causes hyperparathyroidism and periarticular and vascular calcification.

Hyperphosphataemia

Common in CKD

Hypophosphatemia

Can cause muscle (including diaphgram) weakness. (can cause extubation / weaning failure)
Box 9.23 in K and C #TODO

Regulation of bone formation and resorption - bone metabolism

Two types of bone formation

• Intramembranous formation - flat bones including the vault of the skull, most of the upper facial skeleton, parts of the mandible, clavicle, and the pelvis
• Endochondral - axial and appendicular bone

Osteoclasts arise from macrocyte / monocyte lineage.
Cytokines essential for osteoclast function:

• RANKL (receptor activator of nuclear factor kappa B ligand)
• M-SCF (macrocyte colony stimulating factors)

Bone development includes

• modeling - removing bone from one site and deposition at another site (to sculpt bones into the correct shape)
• Remodelling - removing damaged bone and depositing new bone at the same site
• Bone multicellular units are unites of osteoclasts (resorbing bone) and osteoblasts (laying down osteoid) working together (in a fine balance) to remodel bone.
• 
• (red = osteoclasts, blue = osteoblasts)

An oversupply of osteoclasts relative to the need for remodeling or an undersupply of osteoblasts relative to the need for cavity repair are the seminal pathophysiological cellular changes in the most common bone diseases, including osteoporosis

Factors influencing bone turnover

Bone deposition and resorption is influenced by both systemic and local factors.

More complicated than you might think

Fibroblast growth factors - involved in skeletal development. Receptor mutations cause achondroplasia. [[Hormone Physiology#Growth hormone|See Laron Dwarfism]]

Thyroid hormone

Overview of physiology

Synthesis of thyroid hormone

Synthesis occurs in follicular cells
Inorganic iodine -> Oxidation -> incorporation into thyroglobulin -> converted to MIT and DIT
MIT and DIT are converted to T3 and T4. More T4 is produced than T3. --> Bound to TBG (and albumin) --> transported.

[!INFO] only unbound (FREE) thyroid hormones can act on tissues.
only unbound (FREE) thyroid hormones can act on tissues. However, the protein bound fraction is very important for buffering and storage of thyroid hormone to prevent rapid fluctuations.

T3 binds to nuclear recetpor --> Exerts effects

T4 = prohormone (mnemonic "four" rhymes with "pro")
T3 = active metabolite; synthesized from T4 in periphery.

Functions of thyroid hormone

Thyroid hormone binds to it's nuclear receptors.
There are two isoforms - TR alpha and beta, expressed in different tissues.
Receptor-T3 complexes alter gene expression.
Overall effects of T3:
#2022BSQ Q23

Investigation of thyroid function

TSH levels

There is a negative log-linear relationship between serum free T4 and TSH concentrations [1]. This means that very small changes in serum free T4 concentrations induce very large reciprocal changes in serum TSH concentrations. As a result, thyroid function is best assessed by measuring serum TSH, assuming steady-state conditions and the absence of pituitary or hypothalamic disease

Low TSH usually means hyperthyroidism except in

• [[#Sick euthyroid syndrome]]
• Hypopituitarism

High TSH + High fT4 = TSHOma (rare) or Thyroid hormone resistance.
For this situation, administration of TRH (TRH test) will stimulate further TSH releast only in thyroid hormone resistance (TSHOma is autonomic and not controlled by TRH)

Thyroid peroxidase antibodies

Thyroid peroxidase – TPO catalyzes the iodination of tyrosine residues of Tg to form monoiodotyrosine and diiodotyrosine. Nearly all patients with Hashimoto's thyroiditis have high serum concentrations of TPO antibodies.
Also found in 80% of Grave's disease patients.

Hyperthyroidism


3 Common causes

1. Graves
2. TMNG
3. Solitary nodule / adenoma
   See [[Evaluation of hyperthyroidism.png]]

Graves' disease

[!INFO] Is an autoimmume, T cell infiltrative disease.
#2021BSQ-NOV Q32

• Common cause of hyperthyroidism

• Commoner in women - 30 - 60 years.

• Autoimmunity -> TSH-Receptor antibodies (thyrotropin receptor or TRAb) stimulate thyroid gland to make thyroid hormones. -> diffuse, non tender, goiter. (MCQ Point: TSH receptor inhibiting antibodies are also formed)

• Histology: Diffuse, hyperplasia and hypertrophy; follicular cells become tall and columnar with crowding and formation of papillae with no neovascularization. T cell infiltrates are present within thyroid.

• Graves eye disease is a prominent feature. Occurs because of T cell infiltrations;

  • Volume of retro-orbital tissue is increased by 1) T cell infiltration, 2) Inflammatory oedema, 3) Increased extracellular matrix deposition, 4) increased adipocytes.

• Disease follows a relapsing remitting course. Majority have recurrences.

• Associated with other autoimmune diseases like myasthenia, vitiligo, pernicious anaemia

• Patients will usually eventually become hypothyroid.

• Orbitopathy and pretibial myxoedema are not related to thyroxine levels. Pretibial myxoedema is caused by deposition of glycosaminoglycans and T cell infiltration.

Others causes of hyperthyroidism: 

Management of hyperthyroidism

Symptomatic management: Propronolol for beta blockade.
Antithyroid drugs : thionamides: Carbimazole / methimazole and PTU
Methimazole is active metabolite of carbimazole; Equivalent dose of carbimazole is 40% higher.

[!TIP] C --> M: Alphabetical order

[!TIP] Mnemonic
PTU has a T
It's good in T1 of pregnancy
and thyroid STORM
hepaTic Failure

#2022BSQ Q16

Both inhibit thyroid peroxidase which inhibits iodination of tyrosine residues on thyroglobulin.

[!TIP] Pharmacokinetics of carbimazole / methimazole are generally better than PTU.
Carb/methimazole has longer half life.
High intrathyroidal concentrations, outlasting the plasma half life.
More inhibition of iodine organification.

Rash: Usually can be treated with antihistamine, stoppage of thionamide not required. Cross reactivity to different thionamide seen in 50%.

Agranulocytosis:
Thionamides have a high risk of agranulocytosis compared to other drugs that cuase it.
Agranulocytosis occurs within 2-3 months of start of treatment.
If it occurs, treatment with thionamides is contraindicated.

Hypothyroidism

Hashimoto thyroiditis

• COMMONEST CAUSE of hypothyroidism in iodine sufficient areas
• chronic automimmune thyroiditis - months to years.
• commoner in late middle aged women
• Chronic regeneration -> rubbery gland
• Associated with other autoimmune diseases
• Predisposes to thyroid lymphoma
• Histology: lymphocytic and plasma cell infiltration
• Destruction is cell and antibody mediated.

Types of Thyroiditis

Thyroiditis typically causes a painful goiter.

[!TIP] Mnemonic
De quervain - painful
Hasimotos's - chronic

Grand Seikos are japanese watches -> chronic ;)

De quervrain (subacute thyroiditis)

Fundamentaly, a clinical diagnosis.
Neck pain + thyroid tenderness + diffuse goiter usually = subacute thyroiditis.
Thyroid uptake scans will show reduced uptake during the hyperthyroid phase.

Riedels thyroiditis :

Source

fibrous thyroiditis (Reidel's thyroiditis) -> fibrosis of the thyroid gland; woody, hard gland on palpation. Thyroid parenchyma becomes slowly replaced with dense fibroid tissue.
Presentation: Dyspnoea, Dysphagia, hoarseness due to involvement of extrathyroidal structure by the fibrosis.

Sick euthyroid syndrome

Deranged Physiology
T3 : Low (peripheral conversion of T4 to T3 is reduced, therefore T4 may be increased)
TSH : Not elevated (i.e low or normal)
rT3 : elevated (inactive form of T3; Is a T3 antagonist)

Occurs in ill / critically ill patients.
It may be that TSH is physiologically lowered to prevent a catabolic state.
In general, thyroid functions should not be done in critically ill patients because results can be misleading.

Replacement of thyroxine is not helpful in sick euthyroid symdrome. Management is to treat the underlying disease process.

Levothyroxine

Levothyroxine (aka L thyroxine) is synthetic T4.

Prolactin

Prolactin is secreted by lactotroph cells in the anterior pituitary.
Level of secretion of prolantin due to a given stimulus proportional to background hyperplasia of lactotrophs which is driven by oestrogen.
Prolactin secretion by lactotrophs is under tonic inhibition of dopamine (which acts on D2 receptors of the lactotrophs) secreted by the tuberoinfundibular pathway, originating in the arcuate nucleus of the hypothalamus.

Hyperprolactinaemia causes amenorrhoea.
StatPearls prolactin

Causes of hyperprolactinaemia

1. Lactotroph adenoma - usually very high prolactin levels.

   • Relatively common
     • Macroadenoma -> >= 1 cm
   • Even small adenomas can produce large amounts of prolactin
   • Prolactin level is generally proportional to adnoma size.
   • Adenomas are usually composed solely of lactotroph cells.

2. Loss of dopaminergic inhibition

   • Drugs - Commonest : Antipsychotics, verapamil, metoclopramide, domperidone, methyldopa. (NOT with clozapine)
   • Structural problems along the dopamine secreting pathways
     • Tumours of hypothalamus, pituitary stalk, pituitary itself
     • Infitrative diseaseses -> sarcoidosis

Oestrogen tends to increase prolactin levels.

Management of hyperprolactinaemia

Dopamine agonist = cabergoline and bromocriptine.
Cabergoline has less side effects.

Microadenoma -> Dopamine agonist
Macroadenoma -> dopamine agonist -> surgery

Insulin

Production and Secretion of insulin

Increased blood glucose -> uptake of glucose into beta cells by GLUT-2. --> Converted to glucose-6-phosphate by islet specific glucokinase --> takes part in cellular respiration --> increased ATP --> closes ATP dependent pottasium channels --> depolarization --> influx of calcium --> secretion of golgi vessicles.
High serum amino acid also stimulates glucose secretion.

Dysfunction of islet specific glucokinase can cause one type of MODY.

Mechanism of action of insulin

Insulin binds to the insulin receptor -> it has insulin dependent tyrosine kinase activity.

1. Liver ->
   1. inhibits glycogenolysis <- inhibition of Glycogen phosphorylase enzyme
   2. and gluconeogenesis. <- indirect effect (reduced flow of gluconeogenic precursors to the liver etc.)
   3. increases glygogen synthesis <- stimulates glycogen synthase
2. Skeletal muscle + adipose tissue->
   1. Increases glucose uptake <-( Translocation of GLUT-4 to the membrane -> increased glucose uptake)
      1. Under euglycaemic conditions, most of the insulin mediated glucose uptake occurs in muscle.
   2. Increases glycolysis (i.e respiration) <- Stimulation of hexokinase and 6-phosphofructokinase
3. Adipose tissue
   1. inhibits lipolysis <- Inhibition hormone sensitive lipase
   2. Increased triglyceride synthesis <- indirectly by increasing availabiligy of glycerol 3 phosphage due to stimulation of glucose entry and glycolysis
   3. Insulin stimulates adpiose tissue lipoprotein lipase and inhibits muscle lipoprotein lipase (LPL)

[!INFO] Insulin helps to coordinate between different types of fuel used by the body.

Coordination of glucose and lipid metabolism by insulin

1. in the fed stage, insulin secretion promotes glucose utilization AND storage of triglyceride in fat cells.
2. In the fasting state, deficiency of insulin conserves glucose and mobilizes stored triglyceride.

Overall effect of insulin on lipid metabolism = Diversion of TGL from muscle to adipose tissue for storage.
The overall effect of increased triglyceride storage and decreased lipolysis is decreased flux of free fatty acids to the liver. This has indirect but potent action of reducing hepatic gluconeogenesis and hepatic glucose output.

Hypoinsulinaemia:

 Under hypoinsulinemic conditions, such as prolonged fasting or uncontrolled diabetes mellitus, fat mobilization is greatly accelerated, resulting in an oversupply of free fatty acids to the liver. In this situation, the liver synthesizes ketone bodies from the abundant supply of acetyl CoA, a by-product of incomplete beta-oxidation of long-chain fatty acids. => [[General medicine 5#DKA pathophysiology|Diabetic ketoacidosis]]

Other hormones regulating blood glucose level

#2021BSQ-NOV Q07

• Catecholamines increase hepatic glucose output;
• Epinephrine (adrenaline) decreases peripheral uptake of glucose.
  • provides anti-insulin action.
  • Important in type 1 diabetics because they lose the ability to secrete glucagon as well! (protects them against hypoglycaemia)
• Thyroxine: hyperthyroidism exacerbates diabetes. Thyroxine increases gut absorption of glucose and potentiate catecholamine action (which is as above)
• Glucocorticoids: Have a permissive effect on the actions of glucagon and attenuating action on insulin.
  • They are necessary for glucagon mediated gluconeogenesis during fasting.
  • Hypoglycaemic effect of insulin is much stronger (even too strong!) in the absence of glucocorticoids.
  • Both effects above cause hypoglycaemia seen in Addison's disease.
  • The diabetogenic effects are due to increase in protein catabolism, increased gluconeogenesis and decreased peripheral utilization of blucose.
• Exercise: not a hormone BUT
  • Exercise causes upregulation of GLUT-4 transported in muscle and this causes insulin independent increase in glucose uptake.

Glucose transporters

[!TIP] Mnemonic
GLUT-2 and GLUT-4 : even numbered ones are involved in insulin mediated glucose regulation.
1 and 3 are basal, non insulin dependent transporters.

Oestrogen

There are three main types of estrogen: Source

• Estrone (E1): People make this type of estrogen after menopause.
• Estradiol (E2): This is the most common type of estrogen that people make.
• Estriol (E3): This is the main type of estrogen in a pregnant person’s bloodstream. ("trimersters = 3 = estriol")

Cushing's syndrome and Cushing's disease

Features of Cushing's syndrome

1. Osteoporosis
2. Hypertension
3. Facial plethora, proximal myopathy, striae, easy bruising

Commonest cause is iatrogenic;
All glucocorticoids suppress ACTH -> ACTH, and serum cortisol will be low in iatrogenic cushing's syndrome.

The diagnosis of Cushing syndrome is established when at least two different first-line tests are unequivocally abnormal, and physiologic hypercortisolism has been excluded

Sequence of evaluation:

If a patients has feature of Chushing's syndrome

1. It has to be proved that the patient has elevated cortisol
2. The cause of elevated cortisol must be determined.

Initial testing to confirm elevated cortisol:

1. bedtime salivary cortisol

   1. There is a pre-bed time cortisol level nadir in normal physiology.
   2. This is preserved in physiologic hypercortisolism but absent in Cushing's syndrome.

2. 24 hour urinary free cortisol - Measures the total daily cortisol production without being affected by the cyclical variations in it's production.

3. Low dose DST

   1. The low-dose DSTs are standard screening tests to differentiate patients with Cushing syndrome of any cause from patients who do not have Cushing syndrome.
   2. A positive low dose DST will show impaired suppression of cortisol secretion.
   3. The high-dose DSTs are not used to make the diagnosis of Cushing syndrome. (High dose DST is used to identify the source of ACTH if it is abnormally high (i.e Cushing's disease Vs. ectopic ACTH)
   4. There are two forms of low dose DST
      1. Overnight 1mg dexamethasone suppresion test
      2. two day 2 mg DST
   5. Both will show impaired suppression of cortisol if the patient has Cushing's syndrome.

For bedtime salivary cortisol and UFC, two abnormal tests are required.

Pseudo-Cushing's syndrome

If cortisol is found to be elevated with the above preliminary tests, next step is to exclude physiologic hypercortisolism.
AKA - pseudo Cushing syndrome.

Clinically, these patients usually do not have skin or muscle manifestations of Cushing Syndrome.
Causes of pseudo-cushing syndrome (i.e causes of elevated cortisol)

1. #Pregnancy
2. Severe obesity / PCOS
3. Severe major depression
4. Poorly controlled DM
5. OSA

Because of various nuances, the above tests must be unequivocally elevated in order to diagnose Cushing's syndrome. Mild elevations are unlikely to indicate Cushing's syndrome.

Determining the cause of hypercortisolism

Once hypercortisolism has been identified and physiologic hypercortisolism as been excluded, the cause of hypercortisolism must be determined.

First step is determining if the cortisol hypersecretion is
ACTH dependent or ACTH independent.
This is done by measuring ACTH levels.

ACTH levels

Because of cyclical variations, testing at two different times is recommended.

ACTH < 5pg/ML = ACTH independent hypercortisolism

ACTH > 20pg/mL = ACTH dependent hypercortisolism.

ACTH dependent Hypercortisolism

1. The vast majority have pituitary corticotroph adenoma -(CUSHING'S DISEASE)
2. Other causes are ectopic ACTH and ectopic CRH.

Determining the cause of ACTH dependent hypercortisolism

1. CRH stimulation test - differentiates Cushing's disease from all other causes of hypercortisolism
   1. Corticotroph pituitary tumours respond to CRH (despite being tumours) -> AC
2. High dose dexamethason suppression test
   1. Corticotroph tumours are not resistant to negative FB by glucocorticoids
   2. Ectopic ACTH producing tumours have absolutely no inhibition from glucocorticoids. (with the exception of some pulmonar neuroendocrine tumours)
   3. Therefore, 8mg of Dexamethasone oral at 11PM will cause reduction in morning Serum cortisol.
3. Desmopressin stimulation test
   1. Used clinically when CRH is not available
   2. ADH stimulates ACTH release.
   3. Desmopressin is used to mimic this effect. (ADH and desmopressing have a similar action to CRH)
      1. In ACTH secreting adenoma (Cushing's disease) this response is preserved but in ectopic ACTH secreting lesions this response is absent.

Imaging

A mass > 6mm in size in the sella turcica supports a diagnosis of Cushing's disease.
10% of healthy people have masses <6mm in size.

Invasive testing

Sampling the ACTH level from the petrosal sinus can be used if the diagnosis is uncertain.

Adrenaline synthesis

[!TIP] Mnemonic
Dopamine -> Norad -> adrenaline -> ?waste products

Hypothalamus

Is a bilateral collection of nuelcei divided into three zones surrounding the third ventricle and the mammillary bodies.

Gross anatomy


Micro anatomy

Hypopituitarism

[!info] ACTH and TSH are the "hardiest" trophic hormones
Organic pituitary disease affects GH AND GONADOROPHINS >> ACTH AND TSH.
ACTH and TSH are the "hardiest" trophic hormones.
The "G" hormones are more sensitive

Causes of hypopituitarism

[!info] Hypothalamic Vs. Pituitary causes
Pituitary lesions won't reduce ADH secretion but hypothalamic lesions will reduce ADH secretion


Growth hormone

Growth Hormone Physiology

[[2021-Basic Sciences#Glucose regulating hormones|IGF]] <<- Action of IGF

[[Encodrinology MCQ discussion#Growth Hormone disorder diagnosis and investigation]]

Stimulation: GHRH, Ghrelin
Inhibition : Somatostatin

Pattern of secretion:
GH secretion peaks in early puberty
Then gradually decreases.

[!TIP] IGF Vs. GH Vs. Insulin
Despite GH having anti-insulin effects, IGF-1 has insulin like activity

Factors increasing GH secretion

• Peak GH secretory activity occurs within an hour after the onset of deep sleep.
• Exercise
• trauma and sepsis (it's a stress hormone)

Actions of GH

[!Tip] Mnemonic: GH affects all macromolecules - makes things grow

• Lipids -> increase lipolysis
• Proteins -> Increased protein synthesis
• Glucose -> Promotes insulin resistance
• Electrolytes -> Phosphate, salt and water retention
• Bone -> Epiphyseal bone growth

Causes of GH abnormalities

Reduced secretion

In adults, causes are the same as causes of [[Hormone Physiology#Hypopituitarism|hypopituitarism]].
In children, GH deficiency can be caused by various inherited causes as well. (Acquired causes are same as in adults)

Increased secretion

Commonest cause in adults: somatotroph adenoma

Commonest causes in children: Early childhood GH excess is usually due to GHRH excess. (i.e usually not a tumour). They will present with gigantism (or tall stature)

Causes of Increased GH presenting as gigantism (i.e ↑ GH before epiphyseal fusion)
+ Most commonly due to isolated GH excess
+ Could also be due to
+ McCune-albright syndrome - diagnosed in young adults
+ Carney complex - presents in middle aged people
+ MEN 1 and MEN 4 (4th to 5th decates of life)
+ Neurofibromatosis
+ Famlilial isolated pituitar adenomas - autosomal dominant #autosomalDominant

[[Encodrinology MCQ discussion#Growth Hormone disorder diagnosis and investigation|Diagnosis and Investigation of GH disorders]]

Acromegaly

Associated features and pathologic basis

As commonest cause is somatotroph adenoma:
acreomegaly is associated with symptoms caused by pressure effect of adenoma:

1. Headache, bitemporal hemianopia, cranial nerve defects
2. Decreased secretion of other pituitary hormones -> most commonly gonadotrophins
   1. Menstrual dysfunction, vaginal atrophy, galactrorrhea
3. Hyperprolactinaemia - either increased [[#Prolactin]] secretion from the somatotroph adenoma or inhbition of dopaminergic inhibition
4. Effects of GH and IGF-1 Excess:
   1. Soft tissue overgrowth - large tongue, carpal tunnel syndrome + the other classic ones
   2. Joints - Hypertrophic arthorpathy, back pain, kyphosis, hypogonadism induced osteoporosis
   3. Visceral organ enlargement - thyroid, heart, liver, lungs
      1. heart: cardiomyopathy and LVH with diastolic dysfunction and arrhythmias - secondary to hypertension
      2. Hypertension: GH-IGF-I excess -> enhanced sodium- and water retention -> expansion of plasma volume and increased systemic vascular resistance. Source
         3. Hyperinsulinaemia may also stimulate salt and water retention Source
   4. Metabolic - insulin resistance and DM
   5. Sleep apnea
   6. colonic neoplasms

Calcium disorders

[!Info] Hypercalcemia is MUCH more common than hypocalcemia
Usually due to primary hyperparathyroidism; occurs in older females
primary hyperparathyroidism and malignancies = 90% of cases

^da9653

[!WARNING] Hypercalcaemia >>> hypocalcaemia
Hypercalcaemia is much more common than hypocalcaemia

Calcium regulation

Vitamin D

Activated vitamin D (1,25 dihydroxyvitami D) regulated gene transcription by binding to intracellular receptors.

• Its most important biological action is to promote enterocyte differentiation and the intestinal absorption of calcium.
• Other effects include
  • a lesser stimulation of intestinal phosphate absorption
  • direct suppression of parathyroid hormone (PTH) release from the parathyroid gland,
  • regulation of osteoblast function, and
  • permissively allowing PTH-induced osteoclast activation and bone resorption.
    • Illustrative point: "in the elderly, low vitamin D and secondary hyperperparathyroidism reduced bone mineral density" - Kumar & Clark.

^83ab8b

The renal 1-alpha-hydroxylase enzyme which activates vitamin D is primarily regulated by the following factors:

• PTH
• Serum calcium and phosphate concentrations
• Fibroblast growth factor 23 (FGF23)

Activated vitamin D levels are elevated in #pregnancy

The main reason for hypocalcemia in CKD is the impaired activation of vitamin D.

Parathyroid hormone

^0f3395

Functions of Parathyroid hormone

PTH increases renal phosphate excretion and increases plasma calcium by:

• increasing osteoclastic activity in bone (a rapid response)
• increasing intestinal absorption of calcium (a slowerresponse)
• increasing 1α-­hydroxylation of vitamin D (the rate-­limiting step)
• increasing renal tubular reabsorption of calcium.

Parathyroid hormone secretion is directly inhibited by high calcium levels.
This happens through binding of calcium to a GPCR on the parathyroid cells called CaR.

[!INFO] Familial hypo and hypercalcemia
Loss of function mutations of CaR cause chronically elevated Calium levels. (Familial hypocalciuric hypercalcemia. (i.e normal to elevated PTH)
Gain of function mutations of CaR cause familiar hypercalciuric hypocalcemia. (?supressed PTH)

Magnesium is needed for the action of PTH. Hypomagnesaemia impairs PTH release and impairs peripheral organ sensitivity to PTH.

PTH level increases with age, possibly due to declining renal function -> reduced activated Vit D level, declining oestrogen levels and / or declining calcium absorption. Source

Calcitonin

#2021BSQ-NOV Q08

• Produced by parafollicular C cells of the thyroid;
• Despite medullary thyroid CA patients having very high calcitonin levels, their calcium levels are not abnormal.
• Effect: It inhibits osteoclastic bone resorption and increases urinary calcium excretion.
• Calcitonin is elevated in Zollinger-Ellison syndrome and in Pernicious anaemia.
• Calcitonin half life is only 10 minutes.
• Not an important hormone in normal physiology.
• Unlike Vitamin D and PTH, calcitonin is not involved in phosphate homeostasis.
• May be important in pregnancy because it protects the mother's bone against reabsorption when producing milk and providing calcium for foetal bones.

Indications for therapeutic used:

• postmenopausal osteoporosis
• Paget's disease of bone
• Hypercalcemia

Renal handling of calcium

^070bf7

About half of total calcium is protein unbound. The remainder ('complexed' to citrate and phosphate and 'unbound') making up the other half is the 'filtrable' part.
Almost all the filtered calcium is reabsorbed.

PTH and activated vitamin D promote calcium re-absorption in all areas except the PCT. (DCT, TAL, Connecting tubules)
Source

PTH and activated vitamin D promote expression of calcium transport proteins in these regions.
Source ^84acf2

Hypercalcaemia

[[Encodrinology MCQ discussion#Q 10: Hypercalcemia|MCQ discussion]]

Causes are devided into

• paratyroid hormone dependent causes
• parathyroid hormone independent causes
  This is how we should think about each condition below.

malignancy and primary hyperparathyroidism = 90% of cases.

• Primary hyperparathyroidism is the commonest cause of hypercalcaemia by far
  • Ix - Patient has Elevated PTH, Elevated Ca2+ and low PO4 and is asymptomatic. No need for further evaluation
• malignancies including myeloma


Causes of Severe hypercalcaemia :

• malignant disease - One of the causes of symptomatic hypercalcaemia.
• hyperparathyroidism
• chronic kidney disease
• vitamin D therapy.

Investigations for hypercalcaemia

• Serum PTH, Phosphate, Calcium
• 23 h urinary calcium OR single calcium : creatinine ratio. (Do in young patient with moderate incraese in Ca2 level -? familial hypocalciuric hypercalcaemia. (FHH))
  • The CaSR is a member of G protein-coupled receptors and suppresses PTH secretion by sensing high plasma Ca2+ level in the parathyroid glands). In the kidney, the CaSR is most highly expressed in the TAL. Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant disease due to the mutation of CaSR gene, and is manifested as hypercalcemia, hypophosphatemia, parathyroid hyperplasia, and unusually low renal clearance of calcium.Source
• Increased Serum ALP
  • Elevated in severe parathyroid bone disease (i.e PTH is high)
  • but if not (PTH is low) , suggests alternative cause.

Types of Hyperparathyroidism

Primary hyperparathyroidism

• Single adenoma 80%
• Diffuse gland hyperplasia (20%)
• parathyroid carcinoma is rare - causes intractable hypercalcemia
• hyperparathyroidism-jaw tumour syndrome

Secondary hyperparathyroidism

Physiological compensatory mechanism for hypocalcemia.
Therefore, ↑ PTH levels, but normal calcium level.

Tertiary hyperparathyroidism

After chronic secondary hyperparathyroidism, gland becomes autonomous.
↑Ca2+ and ↑↑ Phosphate

Hypocalcaemia

Not very common

Hypoparathyroidism

In hypoparathyroidism, there is increased bone minieral density. But the bone is not properly formed.
So there are increased fractures

Pseudohypoparathyroidism

Caused by a defect in PTH receptor
Biochemical manifestations are just like hypoparathyroidism (Low Ca2+ and high Phosphate)
BUT having HIGH PTH level
Patients have albright phenotype

Pseudo-pseudo hypoparathyroidism

Patients have albright phenotype BUT
All biochemistry is normal

Phosphate and calcium

[!NOTE] What is the relationship between Calcium and Phosphate?
Calcium phosphate is insoluble and Ca and PO4 can remain in solution so long as the solubility product is not exceeded.
In patients with hyperphosphataemia, there is indeed deposition of calcium phosphate. (familiar tumoural calcinosis)
So it makes sense that as a physiological mechamism, PTH increases calcium level and simultaneously decreases phosphate level. to prevent CaPO4 deposition

To illustrate this further:
"The ensuing hyperphosphatemia may induce potentially symptomatic hypocalcemia due to calcium-phosphate precipitation in the tissues." - Source: Hyperphosphatemia

Phosphate physiology

• Directly related to calcium metabolism
• Main storage is bone
• tiny bit in serum
• reabsorption exclusively in the PCT - active process.
  • Reabsorption is reduced by PTH; ∴ ⬆ PTH → ↓Phosphate
  • Osteoblast secreted phosphaturic factors (eg. FGF23- the most studied one) causes ↑ urinary phosphate excretion
  • FGF23 is the earliest marker of abnormal phosphate handling in CKD
  • Inherited defect of FGF23 --> hyperphosphataemia -> familiar tumoural calcinosis

Prolonged hyperphosphataemia causes hyperparathyroidism and periarticular and vascular calcification.

Hyperphosphataemia

Common in CKD

Hypophosphatemia

Can cause muscle (including diaphgram) weakness. (can cause extubation / weaning failure)
Box 9.23 in K and C #TODO

Regulation of bone formation and resorption - bone metabolism

Two types of bone formation

• Intramembranous formation - flat bones including the vault of the skull, most of the upper facial skeleton, parts of the mandible, clavicle, and the pelvis
• Endochondral - axial and appendicular bone

Osteoclasts arise from macrocyte / monocyte lineage.
Cytokines essential for osteoclast function:

• RANKL (receptor activator of nuclear factor kappa B ligand)
• M-SCF (macrocyte colony stimulating factors)

Bone development includes

• modeling - removing bone from one site and deposition at another site (to sculpt bones into the correct shape)
• Remodelling - removing damaged bone and depositing new bone at the same site
• Bone multicellular units are unites of osteoclasts (resorbing bone) and osteoblasts (laying down osteoid) working together (in a fine balance) to remodel bone.
• 
• (red = osteoclasts, blue = osteoblasts)

An oversupply of osteoclasts relative to the need for remodeling or an undersupply of osteoblasts relative to the need for cavity repair are the seminal pathophysiological cellular changes in the most common bone diseases, including osteoporosis

Factors influencing bone turnover

Bone deposition and resorption is influenced by both systemic and local factors.

More complicated than you might think

Fibroblast growth factors - involved in skeletal development. Receptor mutations cause achondroplasia. [[Hormone Physiology#Growth hormone|See Laron Dwarfism]]

Thyroid hormone

Overview of physiology

Synthesis of thyroid hormone

Synthesis occurs in follicular cells
Inorganic iodine -> Oxidation -> incorporation into thyroglobulin -> converted to MIT and DIT
MIT and DIT are converted to T3 and T4. More T4 is produced than T3. --> Bound to TBG (and albumin) --> transported.

[!INFO] only unbound (FREE) thyroid hormones can act on tissues.
only unbound (FREE) thyroid hormones can act on tissues. However, the protein bound fraction is very important for buffering and storage of thyroid hormone to prevent rapid fluctuations.

T3 binds to nuclear recetpor --> Exerts effects

T4 = prohormone (mnemonic "four" rhymes with "pro")
T3 = active metabolite; synthesized from T4 in periphery.

Functions of thyroid hormone

Thyroid hormone binds to it's nuclear receptors.
There are two isoforms - TR alpha and beta, expressed in different tissues.
Receptor-T3 complexes alter gene expression.
Overall effects of T3:
#2022BSQ Q23

Investigation of thyroid function

TSH levels

There is a negative log-linear relationship between serum free T4 and TSH concentrations [1]. This means that very small changes in serum free T4 concentrations induce very large reciprocal changes in serum TSH concentrations. As a result, thyroid function is best assessed by measuring serum TSH, assuming steady-state conditions and the absence of pituitary or hypothalamic disease

Low TSH usually means hyperthyroidism except in

• [[#Sick euthyroid syndrome]]
• Hypopituitarism

High TSH + High fT4 = TSHOma (rare) or Thyroid hormone resistance.
For this situation, administration of TRH (TRH test) will stimulate further TSH releast only in thyroid hormone resistance (TSHOma is autonomic and not controlled by TRH)

Thyroid peroxidase antibodies

Thyroid peroxidase – TPO catalyzes the iodination of tyrosine residues of Tg to form monoiodotyrosine and diiodotyrosine. Nearly all patients with Hashimoto's thyroiditis have high serum concentrations of TPO antibodies.
Also found in 80% of Grave's disease patients.

Hyperthyroidism


3 Common causes

1. Graves
2. TMNG
3. Solitary nodule / adenoma
   See [[Evaluation of hyperthyroidism.png]]

Graves' disease

[!INFO] Is an autoimmume, T cell infiltrative disease.
#2021BSQ-NOV Q32

• Common cause of hyperthyroidism

• Commoner in women - 30 - 60 years.

• Autoimmunity -> TSH-Receptor antibodies (thyrotropin receptor or TRAb) stimulate thyroid gland to make thyroid hormones. -> diffuse, non tender, goiter. (MCQ Point: TSH receptor inhibiting antibodies are also formed)

• Histology: Diffuse, hyperplasia and hypertrophy; follicular cells become tall and columnar with crowding and formation of papillae with no neovascularization. T cell infiltrates are present within thyroid.

• Graves eye disease is a prominent feature. Occurs because of T cell infiltrations;

  • Volume of retro-orbital tissue is increased by 1) T cell infiltration, 2) Inflammatory oedema, 3) Increased extracellular matrix deposition, 4) increased adipocytes.

• Disease follows a relapsing remitting course. Majority have recurrences.

• Associated with other autoimmune diseases like myasthenia, vitiligo, pernicious anaemia

• Patients will usually eventually become hypothyroid.

• Orbitopathy and pretibial myxoedema are not related to thyroxine levels. Pretibial myxoedema is caused by deposition of glycosaminoglycans and T cell infiltration.

Others causes of hyperthyroidism: 

Management of hyperthyroidism

Symptomatic management: Propronolol for beta blockade.
Antithyroid drugs : thionamides: Carbimazole / methimazole and PTU
Methimazole is active metabolite of carbimazole; Equivalent dose of carbimazole is 40% higher.

[!TIP] C --> M: Alphabetical order

[!TIP] Mnemonic
PTU has a T
It's good in T1 of pregnancy
and thyroid STORM
hepaTic Failure

#2022BSQ Q16

Both inhibit thyroid peroxidase which inhibits iodination of tyrosine residues on thyroglobulin.

[!TIP] Pharmacokinetics of carbimazole / methimazole are generally better than PTU.
Carb/methimazole has longer half life.
High intrathyroidal concentrations, outlasting the plasma half life.
More inhibition of iodine organification.

Rash: Usually can be treated with antihistamine, stoppage of thionamide not required. Cross reactivity to different thionamide seen in 50%.

Agranulocytosis:
Thionamides have a high risk of agranulocytosis compared to other drugs that cuase it.
Agranulocytosis occurs within 2-3 months of start of treatment.
If it occurs, treatment with thionamides is contraindicated.

Hypothyroidism

Hashimoto thyroiditis

• COMMONEST CAUSE of hypothyroidism in iodine sufficient areas
• chronic automimmune thyroiditis - months to years.
• commoner in late middle aged women
• Chronic regeneration -> rubbery gland
• Associated with other autoimmune diseases
• Predisposes to thyroid lymphoma
• Histology: lymphocytic and plasma cell infiltration
• Destruction is cell and antibody mediated.

Types of Thyroiditis

Thyroiditis typically causes a painful goiter.

[!TIP] Mnemonic
De quervain - painful
Hasimotos's - chronic

Grand Seikos are japanese watches -> chronic ;)

De quervrain (subacute thyroiditis)

Fundamentaly, a clinical diagnosis.
Neck pain + thyroid tenderness + diffuse goiter usually = subacute thyroiditis.
Thyroid uptake scans will show reduced uptake during the hyperthyroid phase.

Riedels thyroiditis :

Source

fibrous thyroiditis (Reidel's thyroiditis) -> fibrosis of the thyroid gland; woody, hard gland on palpation. Thyroid parenchyma becomes slowly replaced with dense fibroid tissue.
Presentation: Dyspnoea, Dysphagia, hoarseness due to involvement of extrathyroidal structure by the fibrosis.

Sick euthyroid syndrome

Deranged Physiology
T3 : Low (peripheral conversion of T4 to T3 is reduced, therefore T4 may be increased)
TSH : Not elevated (i.e low or normal)
rT3 : elevated (inactive form of T3; Is a T3 antagonist)

Occurs in ill / critically ill patients.
It may be that TSH is physiologically lowered to prevent a catabolic state.
In general, thyroid functions should not be done in critically ill patients because results can be misleading.

Replacement of thyroxine is not helpful in sick euthyroid symdrome. Management is to treat the underlying disease process.

Levothyroxine

Levothyroxine (aka L thyroxine) is synthetic T4.

Prolactin

Prolactin is secreted by lactotroph cells in the anterior pituitary.
Level of secretion of prolantin due to a given stimulus proportional to background hyperplasia of lactotrophs which is driven by oestrogen.
Prolactin secretion by lactotrophs is under tonic inhibition of dopamine (which acts on D2 receptors of the lactotrophs) secreted by the tuberoinfundibular pathway, originating in the arcuate nucleus of the hypothalamus.

Hyperprolactinaemia causes amenorrhoea.
StatPearls prolactin

Causes of hyperprolactinaemia

1. Lactotroph adenoma - usually very high prolactin levels.

   • Relatively common
     • Macroadenoma -> >= 1 cm
   • Even small adenomas can produce large amounts of prolactin
   • Prolactin level is generally proportional to adnoma size.
   • Adenomas are usually composed solely of lactotroph cells.

2. Loss of dopaminergic inhibition

   • Drugs - Commonest : Antipsychotics, verapamil, metoclopramide, domperidone, methyldopa. (NOT with clozapine)
   • Structural problems along the dopamine secreting pathways
     • Tumours of hypothalamus, pituitary stalk, pituitary itself
     • Infitrative diseaseses -> sarcoidosis

Oestrogen tends to increase prolactin levels.

Management of hyperprolactinaemia

Dopamine agonist = cabergoline and bromocriptine.
Cabergoline has less side effects.

Microadenoma -> Dopamine agonist
Macroadenoma -> dopamine agonist -> surgery

Insulin

Production and Secretion of insulin

Increased blood glucose -> uptake of glucose into beta cells by GLUT-2. --> Converted to glucose-6-phosphate by islet specific glucokinase --> takes part in cellular respiration --> increased ATP --> closes ATP dependent pottasium channels --> depolarization --> influx of calcium --> secretion of golgi vessicles.
High serum amino acid also stimulates glucose secretion.

Dysfunction of islet specific glucokinase can cause one type of MODY.

Mechanism of action of insulin

Insulin binds to the insulin receptor -> it has insulin dependent tyrosine kinase activity.

1. Liver ->
   1. inhibits glycogenolysis <- inhibition of Glycogen phosphorylase enzyme
   2. and gluconeogenesis. <- indirect effect (reduced flow of gluconeogenic precursors to the liver etc.)
   3. increases glygogen synthesis <- stimulates glycogen synthase
2. Skeletal muscle + adipose tissue->
   1. Increases glucose uptake <-( Translocation of GLUT-4 to the membrane -> increased glucose uptake)
      1. Under euglycaemic conditions, most of the insulin mediated glucose uptake occurs in muscle.
   2. Increases glycolysis (i.e respiration) <- Stimulation of hexokinase and 6-phosphofructokinase
3. Adipose tissue
   1. inhibits lipolysis <- Inhibition hormone sensitive lipase
   2. Increased triglyceride synthesis <- indirectly by increasing availabiligy of glycerol 3 phosphage due to stimulation of glucose entry and glycolysis
   3. Insulin stimulates adpiose tissue lipoprotein lipase and inhibits muscle lipoprotein lipase (LPL)

[!INFO] Insulin helps to coordinate between different types of fuel used by the body.

Coordination of glucose and lipid metabolism by insulin

1. in the fed stage, insulin secretion promotes glucose utilization AND storage of triglyceride in fat cells.
2. In the fasting state, deficiency of insulin conserves glucose and mobilizes stored triglyceride.

Overall effect of insulin on lipid metabolism = Diversion of TGL from muscle to adipose tissue for storage.
The overall effect of increased triglyceride storage and decreased lipolysis is decreased flux of free fatty acids to the liver. This has indirect but potent action of reducing hepatic gluconeogenesis and hepatic glucose output.

Hypoinsulinaemia:

 Under hypoinsulinemic conditions, such as prolonged fasting or uncontrolled diabetes mellitus, fat mobilization is greatly accelerated, resulting in an oversupply of free fatty acids to the liver. In this situation, the liver synthesizes ketone bodies from the abundant supply of acetyl CoA, a by-product of incomplete beta-oxidation of long-chain fatty acids. => [[General medicine 5#DKA pathophysiology|Diabetic ketoacidosis]]

Other hormones regulating blood glucose level

#2021BSQ-NOV Q07

• Catecholamines increase hepatic glucose output;
• Epinephrine (adrenaline) decreases peripheral uptake of glucose.
  • provides anti-insulin action.
  • Important in type 1 diabetics because they lose the ability to secrete glucagon as well! (protects them against hypoglycaemia)
• Thyroxine: hyperthyroidism exacerbates diabetes. Thyroxine increases gut absorption of glucose and potentiate catecholamine action (which is as above)
• Glucocorticoids: Have a permissive effect on the actions of glucagon and attenuating action on insulin.
  • They are necessary for glucagon mediated gluconeogenesis during fasting.
  • Hypoglycaemic effect of insulin is much stronger (even too strong!) in the absence of glucocorticoids.
  • Both effects above cause hypoglycaemia seen in Addison's disease.
  • The diabetogenic effects are due to increase in protein catabolism, increased gluconeogenesis and decreased peripheral utilization of blucose.
• Exercise: not a hormone BUT
  • Exercise causes upregulation of GLUT-4 transported in muscle and this causes insulin independent increase in glucose uptake.

Glucose transporters

[!TIP] Mnemonic
GLUT-2 and GLUT-4 : even numbered ones are involved in insulin mediated glucose regulation.
1 and 3 are basal, non insulin dependent transporters.

Oestrogen

There are three main types of estrogen: Source

• Estrone (E1): People make this type of estrogen after menopause.
• Estradiol (E2): This is the most common type of estrogen that people make.
• Estriol (E3): This is the main type of estrogen in a pregnant person’s bloodstream. ("trimersters = 3 = estriol")

Cushing's syndrome and Cushing's disease

Features of Cushing's syndrome

1. Osteoporosis
2. Hypertension
3. Facial plethora, proximal myopathy, striae, easy bruising

Commonest cause is iatrogenic;
All glucocorticoids suppress ACTH -> ACTH, and serum cortisol will be low in iatrogenic cushing's syndrome.

The diagnosis of Cushing syndrome is established when at least two different first-line tests are unequivocally abnormal, and physiologic hypercortisolism has been excluded

Sequence of evaluation:

If a patients has feature of Chushing's syndrome

1. It has to be proved that the patient has elevated cortisol
2. The cause of elevated cortisol must be determined.

Initial testing to confirm elevated cortisol:

1. bedtime salivary cortisol

   1. There is a pre-bed time cortisol level nadir in normal physiology.
   2. This is preserved in physiologic hypercortisolism but absent in Cushing's syndrome.

2. 24 hour urinary free cortisol - Measures the total daily cortisol production without being affected by the cyclical variations in it's production.

3. Low dose DST

   1. The low-dose DSTs are standard screening tests to differentiate patients with Cushing syndrome of any cause from patients who do not have Cushing syndrome.
   2. A positive low dose DST will show impaired suppression of cortisol secretion.
   3. The high-dose DSTs are not used to make the diagnosis of Cushing syndrome. (High dose DST is used to identify the source of ACTH if it is abnormally high (i.e Cushing's disease Vs. ectopic ACTH)
   4. There are two forms of low dose DST
      1. Overnight 1mg dexamethasone suppresion test
      2. two day 2 mg DST
   5. Both will show impaired suppression of cortisol if the patient has Cushing's syndrome.

For bedtime salivary cortisol and UFC, two abnormal tests are required.

Pseudo-Cushing's syndrome

If cortisol is found to be elevated with the above preliminary tests, next step is to exclude physiologic hypercortisolism.
AKA - pseudo Cushing syndrome.

Clinically, these patients usually do not have skin or muscle manifestations of Cushing Syndrome.
Causes of pseudo-cushing syndrome (i.e causes of elevated cortisol)

1. #Pregnancy
2. Severe obesity / PCOS
3. Severe major depression
4. Poorly controlled DM
5. OSA

Because of various nuances, the above tests must be unequivocally elevated in order to diagnose Cushing's syndrome. Mild elevations are unlikely to indicate Cushing's syndrome.

Determining the cause of hypercortisolism

Once hypercortisolism has been identified and physiologic hypercortisolism as been excluded, the cause of hypercortisolism must be determined.

First step is determining if the cortisol hypersecretion is
ACTH dependent or ACTH independent.
This is done by measuring ACTH levels.

ACTH levels

Because of cyclical variations, testing at two different times is recommended.

ACTH < 5pg/ML = ACTH independent hypercortisolism

ACTH > 20pg/mL = ACTH dependent hypercortisolism.

ACTH dependent Hypercortisolism

1. The vast majority have pituitary corticotroph adenoma -(CUSHING'S DISEASE)
2. Other causes are ectopic ACTH and ectopic CRH.

Determining the cause of ACTH dependent hypercortisolism

1. CRH stimulation test - differentiates Cushing's disease from all other causes of hypercortisolism
   1. Corticotroph pituitary tumours respond to CRH (despite being tumours) -> AC
2. High dose dexamethason suppression test
   1. Corticotroph tumours are not resistant to negative FB by glucocorticoids
   2. Ectopic ACTH producing tumours have absolutely no inhibition from glucocorticoids. (with the exception of some pulmonar neuroendocrine tumours)
   3. Therefore, 8mg of Dexamethasone oral at 11PM will cause reduction in morning Serum cortisol.
3. Desmopressin stimulation test
   1. Used clinically when CRH is not available
   2. ADH stimulates ACTH release.
   3. Desmopressin is used to mimic this effect. (ADH and desmopressing have a similar action to CRH)
      1. In ACTH secreting adenoma (Cushing's disease) this response is preserved but in ectopic ACTH secreting lesions this response is absent.

Imaging

A mass > 6mm in size in the sella turcica supports a diagnosis of Cushing's disease.
10% of healthy people have masses <6mm in size.

Invasive testing

Sampling the ACTH level from the petrosal sinus can be used if the diagnosis is uncertain.

Adrenaline synthesis

[!TIP] Mnemonic
Dopamine -> Norad -> adrenaline -> ?waste products

Hypothalamus

Is a bilateral collection of nuelcei divided into three zones surrounding the third ventricle and the mammillary bodies.

Gross anatomy


Micro anatomy

Hypopituitarism

[!info] ACTH and TSH are the "hardiest" trophic hormones
Organic pituitary disease affects GH AND GONADOROPHINS >> ACTH AND TSH.
ACTH and TSH are the "hardiest" trophic hormones.
The "G" hormones are more sensitive

Causes of hypopituitarism

[!info] Hypothalamic Vs. Pituitary causes
Pituitary lesions won't reduce ADH secretion but hypothalamic lesions will reduce ADH secretion


Growth hormone

Growth Hormone Physiology

[[2021-Basic Sciences#Glucose regulating hormones|IGF]] <<- Action of IGF

[[Encodrinology MCQ discussion#Growth Hormone disorder diagnosis and investigation]]

Stimulation: GHRH, Ghrelin
Inhibition : Somatostatin

Pattern of secretion:
GH secretion peaks in early puberty
Then gradually decreases.

[!TIP] IGF Vs. GH Vs. Insulin
Despite GH having anti-insulin effects, IGF-1 has insulin like activity

Factors increasing GH secretion

• Peak GH secretory activity occurs within an hour after the onset of deep sleep.
• Exercise
• trauma and sepsis (it's a stress hormone)

Actions of GH

[!Tip] Mnemonic: GH affects all macromolecules - makes things grow

• Lipids -> increase lipolysis
• Proteins -> Increased protein synthesis
• Glucose -> Promotes insulin resistance
• Electrolytes -> Phosphate, salt and water retention
• Bone -> Epiphyseal bone growth

Causes of GH abnormalities

Reduced secretion

In adults, causes are the same as causes of [[Hormone Physiology#Hypopituitarism|hypopituitarism]].
In children, GH deficiency can be caused by various inherited causes as well. (Acquired causes are same as in adults)

Increased secretion

Commonest cause in adults: somatotroph adenoma

Commonest causes in children: Early childhood GH excess is usually due to GHRH excess. (i.e usually not a tumour). They will present with gigantism (or tall stature)

Causes of Increased GH presenting as gigantism (i.e ↑ GH before epiphyseal fusion)
+ Most commonly due to isolated GH excess
+ Could also be due to
+ McCune-albright syndrome - diagnosed in young adults
+ Carney complex - presents in middle aged people
+ MEN 1 and MEN 4 (4th to 5th decates of life)
+ Neurofibromatosis
+ Famlilial isolated pituitar adenomas - autosomal dominant #autosomalDominant

[[Encodrinology MCQ discussion#Growth Hormone disorder diagnosis and investigation|Diagnosis and Investigation of GH disorders]]

Acromegaly

Associated features and pathologic basis

As commonest cause is somatotroph adenoma:
acreomegaly is associated with symptoms caused by pressure effect of adenoma:

1. Headache, bitemporal hemianopia, cranial nerve defects
2. Decreased secretion of other pituitary hormones -> most commonly gonadotrophins
   1. Menstrual dysfunction, vaginal atrophy, galactrorrhea
3. Hyperprolactinaemia - either increased [[#Prolactin]] secretion from the somatotroph adenoma or inhbition of dopaminergic inhibition
4. Effects of GH and IGF-1 Excess:
   1. Soft tissue overgrowth - large tongue, carpal tunnel syndrome + the other classic ones
   2. Joints - Hypertrophic arthorpathy, back pain, kyphosis, hypogonadism induced osteoporosis
   3. Visceral organ enlargement - thyroid, heart, liver, lungs
      1. heart: cardiomyopathy and LVH with diastolic dysfunction and arrhythmias - secondary to hypertension
      2. Hypertension: GH-IGF-I excess -> enhanced sodium- and water retention -> expansion of plasma volume and increased systemic vascular resistance. Source
         3. Hyperinsulinaemia may also stimulate salt and water retention Source
   4. Metabolic - insulin resistance and DM
   5. Sleep apnea
   6. colonic neoplasms

Calcium disorders

[!Info] Hypercalcemia is MUCH more common than hypocalcemia
Usually due to primary hyperparathyroidism; occurs in older females
primary hyperparathyroidism and malignancies = 90% of cases

^da9653

[!WARNING] Hypercalcaemia >>> hypocalcaemia
Hypercalcaemia is much more common than hypocalcaemia

Calcium regulation

Vitamin D

Activated vitamin D (1,25 dihydroxyvitami D) regulated gene transcription by binding to intracellular receptors.

• Its most important biological action is to promote enterocyte differentiation and the intestinal absorption of calcium.
• Other effects include
  • a lesser stimulation of intestinal phosphate absorption
  • direct suppression of parathyroid hormone (PTH) release from the parathyroid gland,
  • regulation of osteoblast function, and
  • permissively allowing PTH-induced osteoclast activation and bone resorption.
    • Illustrative point: "in the elderly, low vitamin D and secondary hyperperparathyroidism reduced bone mineral density" - Kumar & Clark.

^83ab8b

The renal 1-alpha-hydroxylase enzyme which activates vitamin D is primarily regulated by the following factors:

• PTH
• Serum calcium and phosphate concentrations
• Fibroblast growth factor 23 (FGF23)

Activated vitamin D levels are elevated in #pregnancy

The main reason for hypocalcemia in CKD is the impaired activation of vitamin D.

Parathyroid hormone

^0f3395

Functions of Parathyroid hormone

PTH increases renal phosphate excretion and increases plasma calcium by:

• increasing osteoclastic activity in bone (a rapid response)
• increasing intestinal absorption of calcium (a slowerresponse)
• increasing 1α-­hydroxylation of vitamin D (the rate-­limiting step)
• increasing renal tubular reabsorption of calcium.

Parathyroid hormone secretion is directly inhibited by high calcium levels.
This happens through binding of calcium to a GPCR on the parathyroid cells called CaR.

[!INFO] Familial hypo and hypercalcemia
Loss of function mutations of CaR cause chronically elevated Calium levels. (Familial hypocalciuric hypercalcemia. (i.e normal to elevated PTH)
Gain of function mutations of CaR cause familiar hypercalciuric hypocalcemia. (?supressed PTH)

Magnesium is needed for the action of PTH. Hypomagnesaemia impairs PTH release and impairs peripheral organ sensitivity to PTH.

PTH level increases with age, possibly due to declining renal function -> reduced activated Vit D level, declining oestrogen levels and / or declining calcium absorption. Source

Calcitonin

#2021BSQ-NOV Q08

• Produced by parafollicular C cells of the thyroid;
• Despite medullary thyroid CA patients having very high calcitonin levels, their calcium levels are not abnormal.
• Effect: It inhibits osteoclastic bone resorption and increases urinary calcium excretion.
• Calcitonin is elevated in Zollinger-Ellison syndrome and in Pernicious anaemia.
• Calcitonin half life is only 10 minutes.
• Not an important hormone in normal physiology.
• Unlike Vitamin D and PTH, calcitonin is not involved in phosphate homeostasis.
• May be important in pregnancy because it protects the mother's bone against reabsorption when producing milk and providing calcium for foetal bones.

Indications for therapeutic used:

• postmenopausal osteoporosis
• Paget's disease of bone
• Hypercalcemia

Renal handling of calcium

^070bf7

About half of total calcium is protein unbound. The remainder ('complexed' to citrate and phosphate and 'unbound') making up the other half is the 'filtrable' part.
Almost all the filtered calcium is reabsorbed.

PTH and activated vitamin D promote calcium re-absorption in all areas except the PCT. (DCT, TAL, Connecting tubules)
Source

PTH and activated vitamin D promote expression of calcium transport proteins in these regions.
Source ^84acf2

Hypercalcaemia

[[Encodrinology MCQ discussion#Q 10: Hypercalcemia|MCQ discussion]]

Causes are devided into

• paratyroid hormone dependent causes
• parathyroid hormone independent causes
  This is how we should think about each condition below.

malignancy and primary hyperparathyroidism = 90% of cases.

• Primary hyperparathyroidism is the commonest cause of hypercalcaemia by far
  • Ix - Patient has Elevated PTH, Elevated Ca2+ and low PO4 and is asymptomatic. No need for further evaluation
• malignancies including myeloma


Causes of Severe hypercalcaemia :

• malignant disease - One of the causes of symptomatic hypercalcaemia.
• hyperparathyroidism
• chronic kidney disease
• vitamin D therapy.

Investigations for hypercalcaemia

• Serum PTH, Phosphate, Calcium
• 23 h urinary calcium OR single calcium : creatinine ratio. (Do in young patient with moderate incraese in Ca2 level -? familial hypocalciuric hypercalcaemia. (FHH))
  • The CaSR is a member of G protein-coupled receptors and suppresses PTH secretion by sensing high plasma Ca2+ level in the parathyroid glands). In the kidney, the CaSR is most highly expressed in the TAL. Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant disease due to the mutation of CaSR gene, and is manifested as hypercalcemia, hypophosphatemia, parathyroid hyperplasia, and unusually low renal clearance of calcium.Source
• Increased Serum ALP
  • Elevated in severe parathyroid bone disease (i.e PTH is high)
  • but if not (PTH is low) , suggests alternative cause.

Types of Hyperparathyroidism

Primary hyperparathyroidism

• Single adenoma 80%
• Diffuse gland hyperplasia (20%)
• parathyroid carcinoma is rare - causes intractable hypercalcemia
• hyperparathyroidism-jaw tumour syndrome

Secondary hyperparathyroidism

Physiological compensatory mechanism for hypocalcemia.
Therefore, ↑ PTH levels, but normal calcium level.

Tertiary hyperparathyroidism

After chronic secondary hyperparathyroidism, gland becomes autonomous.
↑Ca2+ and ↑↑ Phosphate

Hypocalcaemia

Not very common

Hypoparathyroidism

In hypoparathyroidism, there is increased bone minieral density. But the bone is not properly formed.
So there are increased fractures

Pseudohypoparathyroidism

Caused by a defect in PTH receptor
Biochemical manifestations are just like hypoparathyroidism (Low Ca2+ and high Phosphate)
BUT having HIGH PTH level
Patients have albright phenotype

Pseudo-pseudo hypoparathyroidism

Patients have albright phenotype BUT
All biochemistry is normal

Phosphate and calcium

[!NOTE] What is the relationship between Calcium and Phosphate?
Calcium phosphate is insoluble and Ca and PO4 can remain in solution so long as the solubility product is not exceeded.
In patients with hyperphosphataemia, there is indeed deposition of calcium phosphate. (familiar tumoural calcinosis)
So it makes sense that as a physiological mechamism, PTH increases calcium level and simultaneously decreases phosphate level. to prevent CaPO4 deposition

To illustrate this further:
"The ensuing hyperphosphatemia may induce potentially symptomatic hypocalcemia due to calcium-phosphate precipitation in the tissues." - Source: Hyperphosphatemia

Phosphate physiology

• Directly related to calcium metabolism
• Main storage is bone
• tiny bit in serum
• reabsorption exclusively in the PCT - active process.
  • Reabsorption is reduced by PTH; ∴ ⬆ PTH → ↓Phosphate
  • Osteoblast secreted phosphaturic factors (eg. FGF23- the most studied one) causes ↑ urinary phosphate excretion
  • FGF23 is the earliest marker of abnormal phosphate handling in CKD
  • Inherited defect of FGF23 --> hyperphosphataemia -> familiar tumoural calcinosis

Prolonged hyperphosphataemia causes hyperparathyroidism and periarticular and vascular calcification.

Hyperphosphataemia

Common in CKD

Hypophosphatemia

Can cause muscle (including diaphgram) weakness. (can cause extubation / weaning failure)
Box 9.23 in K and C #TODO

Regulation of bone formation and resorption - bone metabolism

Two types of bone formation

• Intramembranous formation - flat bones including the vault of the skull, most of the upper facial skeleton, parts of the mandible, clavicle, and the pelvis
• Endochondral - axial and appendicular bone

Osteoclasts arise from macrocyte / monocyte lineage.
Cytokines essential for osteoclast function:

• RANKL (receptor activator of nuclear factor kappa B ligand)
• M-SCF (macrocyte colony stimulating factors)

Bone development includes

• modeling - removing bone from one site and deposition at another site (to sculpt bones into the correct shape)
• Remodelling - removing damaged bone and depositing new bone at the same site
• Bone multicellular units are unites of osteoclasts (resorbing bone) and osteoblasts (laying down osteoid) working together (in a fine balance) to remodel bone.
• 
• (red = osteoclasts, blue = osteoblasts)

An oversupply of osteoclasts relative to the need for remodeling or an undersupply of osteoblasts relative to the need for cavity repair are the seminal pathophysiological cellular changes in the most common bone diseases, including osteoporosis

Factors influencing bone turnover

Bone deposition and resorption is influenced by both systemic and local factors.

More complicated than you might think

Fibroblast growth factors - involved in skeletal development. Receptor mutations cause achondroplasia. [[Hormone Physiology#Growth hormone|See Laron Dwarfism]]

Thyroid hormone

Overview of physiology

Synthesis of thyroid hormone

Synthesis occurs in follicular cells
Inorganic iodine -> Oxidation -> incorporation into thyroglobulin -> converted to MIT and DIT
MIT and DIT are converted to T3 and T4. More T4 is produced than T3. --> Bound to TBG (and albumin) --> transported.

[!INFO] only unbound (FREE) thyroid hormones can act on tissues.
only unbound (FREE) thyroid hormones can act on tissues. However, the protein bound fraction is very important for buffering and storage of thyroid hormone to prevent rapid fluctuations.

T3 binds to nuclear recetpor --> Exerts effects

T4 = prohormone (mnemonic "four" rhymes with "pro")
T3 = active metabolite; synthesized from T4 in periphery.

Functions of thyroid hormone

Thyroid hormone binds to it's nuclear receptors.
There are two isoforms - TR alpha and beta, expressed in different tissues.
Receptor-T3 complexes alter gene expression.
Overall effects of T3:
#2022BSQ Q23

Investigation of thyroid function

TSH levels

There is a negative log-linear relationship between serum free T4 and TSH concentrations [1]. This means that very small changes in serum free T4 concentrations induce very large reciprocal changes in serum TSH concentrations. As a result, thyroid function is best assessed by measuring serum TSH, assuming steady-state conditions and the absence of pituitary or hypothalamic disease

Low TSH usually means hyperthyroidism except in

• [[#Sick euthyroid syndrome]]
• Hypopituitarism

High TSH + High fT4 = TSHOma (rare) or Thyroid hormone resistance.
For this situation, administration of TRH (TRH test) will stimulate further TSH releast only in thyroid hormone resistance (TSHOma is autonomic and not controlled by TRH)

Thyroid peroxidase antibodies

Thyroid peroxidase – TPO catalyzes the iodination of tyrosine residues of Tg to form monoiodotyrosine and diiodotyrosine. Nearly all patients with Hashimoto's thyroiditis have high serum concentrations of TPO antibodies.
Also found in 80% of Grave's disease patients.

Hyperthyroidism


3 Common causes

1. Graves
2. TMNG
3. Solitary nodule / adenoma
   See [[Evaluation of hyperthyroidism.png]]

Graves' disease

[!INFO] Is an autoimmume, T cell infiltrative disease.
#2021BSQ-NOV Q32

• Common cause of hyperthyroidism

• Commoner in women - 30 - 60 years.

• Autoimmunity -> TSH-Receptor antibodies (thyrotropin receptor or TRAb) stimulate thyroid gland to make thyroid hormones. -> diffuse, non tender, goiter. (MCQ Point: TSH receptor inhibiting antibodies are also formed)

• Histology: Diffuse, hyperplasia and hypertrophy; follicular cells become tall and columnar with crowding and formation of papillae with no neovascularization. T cell infiltrates are present within thyroid.

• Graves eye disease is a prominent feature. Occurs because of T cell infiltrations;

  • Volume of retro-orbital tissue is increased by 1) T cell infiltration, 2) Inflammatory oedema, 3) Increased extracellular matrix deposition, 4) increased adipocytes.

• Disease follows a relapsing remitting course. Majority have recurrences.

• Associated with other autoimmune diseases like myasthenia, vitiligo, pernicious anaemia

• Patients will usually eventually become hypothyroid.

• Orbitopathy and pretibial myxoedema are not related to thyroxine levels. Pretibial myxoedema is caused by deposition of glycosaminoglycans and T cell infiltration.

Others causes of hyperthyroidism: 

Management of hyperthyroidism

Symptomatic management: Propronolol for beta blockade.
Antithyroid drugs : thionamides: Carbimazole / methimazole and PTU
Methimazole is active metabolite of carbimazole; Equivalent dose of carbimazole is 40% higher.

[!TIP] C --> M: Alphabetical order

[!TIP] Mnemonic
PTU has a T
It's good in T1 of pregnancy
and thyroid STORM
hepaTic Failure

#2022BSQ Q16

Both inhibit thyroid peroxidase which inhibits iodination of tyrosine residues on thyroglobulin.

[!TIP] Pharmacokinetics of carbimazole / methimazole are generally better than PTU.
Carb/methimazole has longer half life.
High intrathyroidal concentrations, outlasting the plasma half life.
More inhibition of iodine organification.

Rash: Usually can be treated with antihistamine, stoppage of thionamide not required. Cross reactivity to different thionamide seen in 50%.

Agranulocytosis:
Thionamides have a high risk of agranulocytosis compared to other drugs that cuase it.
Agranulocytosis occurs within 2-3 months of start of treatment.
If it occurs, treatment with thionamides is contraindicated.

Hypothyroidism

Hashimoto thyroiditis

• COMMONEST CAUSE of hypothyroidism in iodine sufficient areas
• chronic automimmune thyroiditis - months to years.
• commoner in late middle aged women
• Chronic regeneration -> rubbery gland
• Associated with other autoimmune diseases
• Predisposes to thyroid lymphoma
• Histology: lymphocytic and plasma cell infiltration
• Destruction is cell and antibody mediated.

Types of Thyroiditis

Thyroiditis typically causes a painful goiter.

[!TIP] Mnemonic
De quervain - painful
Hasimotos's - chronic

Grand Seikos are japanese watches -> chronic ;)

De quervrain (subacute thyroiditis)

Fundamentaly, a clinical diagnosis.
Neck pain + thyroid tenderness + diffuse goiter usually = subacute thyroiditis.
Thyroid uptake scans will show reduced uptake during the hyperthyroid phase.

Riedels thyroiditis :

Source

fibrous thyroiditis (Reidel's thyroiditis) -> fibrosis of the thyroid gland; woody, hard gland on palpation. Thyroid parenchyma becomes slowly replaced with dense fibroid tissue.
Presentation: Dyspnoea, Dysphagia, hoarseness due to involvement of extrathyroidal structure by the fibrosis.

Sick euthyroid syndrome

Deranged Physiology
T3 : Low (peripheral conversion of T4 to T3 is reduced, therefore T4 may be increased)
TSH : Not elevated (i.e low or normal)
rT3 : elevated (inactive form of T3; Is a T3 antagonist)

Occurs in ill / critically ill patients.
It may be that TSH is physiologically lowered to prevent a catabolic state.
In general, thyroid functions should not be done in critically ill patients because results can be misleading.

Replacement of thyroxine is not helpful in sick euthyroid symdrome. Management is to treat the underlying disease process.

Levothyroxine

Levothyroxine (aka L thyroxine) is synthetic T4.

Prolactin

Prolactin is secreted by lactotroph cells in the anterior pituitary.
Level of secretion of prolantin due to a given stimulus proportional to background hyperplasia of lactotrophs which is driven by oestrogen.
Prolactin secretion by lactotrophs is under tonic inhibition of dopamine (which acts on D2 receptors of the lactotrophs) secreted by the tuberoinfundibular pathway, originating in the arcuate nucleus of the hypothalamus.

Hyperprolactinaemia causes amenorrhoea.
StatPearls prolactin

Causes of hyperprolactinaemia

1. Lactotroph adenoma - usually very high prolactin levels.

   • Relatively common
     • Macroadenoma -> >= 1 cm
   • Even small adenomas can produce large amounts of prolactin
   • Prolactin level is generally proportional to adnoma size.
   • Adenomas are usually composed solely of lactotroph cells.

2. Loss of dopaminergic inhibition

   • Drugs - Commonest : Antipsychotics, verapamil, metoclopramide, domperidone, methyldopa. (NOT with clozapine)
   • Structural problems along the dopamine secreting pathways
     • Tumours of hypothalamus, pituitary stalk, pituitary itself
     • Infitrative diseaseses -> sarcoidosis

Oestrogen tends to increase prolactin levels.

Management of hyperprolactinaemia

Dopamine agonist = cabergoline and bromocriptine.
Cabergoline has less side effects.

Microadenoma -> Dopamine agonist
Macroadenoma -> dopamine agonist -> surgery

Insulin

Production and Secretion of insulin

Increased blood glucose -> uptake of glucose into beta cells by GLUT-2. --> Converted to glucose-6-phosphate by islet specific glucokinase --> takes part in cellular respiration --> increased ATP --> closes ATP dependent pottasium channels --> depolarization --> influx of calcium --> secretion of golgi vessicles.
High serum amino acid also stimulates glucose secretion.

Dysfunction of islet specific glucokinase can cause one type of MODY.

Mechanism of action of insulin

Insulin binds to the insulin receptor -> it has insulin dependent tyrosine kinase activity.

1. Liver ->
   1. inhibits glycogenolysis <- inhibition of Glycogen phosphorylase enzyme
   2. and gluconeogenesis. <- indirect effect (reduced flow of gluconeogenic precursors to the liver etc.)
   3. increases glygogen synthesis <- stimulates glycogen synthase
2. Skeletal muscle + adipose tissue->
   1. Increases glucose uptake <-( Translocation of GLUT-4 to the membrane -> increased glucose uptake)
      1. Under euglycaemic conditions, most of the insulin mediated glucose uptake occurs in muscle.
   2. Increases glycolysis (i.e respiration) <- Stimulation of hexokinase and 6-phosphofructokinase
3. Adipose tissue
   1. inhibits lipolysis <- Inhibition hormone sensitive lipase
   2. Increased triglyceride synthesis <- indirectly by increasing availabiligy of glycerol 3 phosphage due to stimulation of glucose entry and glycolysis
   3. Insulin stimulates adpiose tissue lipoprotein lipase and inhibits muscle lipoprotein lipase (LPL)

[!INFO] Insulin helps to coordinate between different types of fuel used by the body.

Coordination of glucose and lipid metabolism by insulin

1. in the fed stage, insulin secretion promotes glucose utilization AND storage of triglyceride in fat cells.
2. In the fasting state, deficiency of insulin conserves glucose and mobilizes stored triglyceride.

Overall effect of insulin on lipid metabolism = Diversion of TGL from muscle to adipose tissue for storage.
The overall effect of increased triglyceride storage and decreased lipolysis is decreased flux of free fatty acids to the liver. This has indirect but potent action of reducing hepatic gluconeogenesis and hepatic glucose output.

Hypoinsulinaemia:

 Under hypoinsulinemic conditions, such as prolonged fasting or uncontrolled diabetes mellitus, fat mobilization is greatly accelerated, resulting in an oversupply of free fatty acids to the liver. In this situation, the liver synthesizes ketone bodies from the abundant supply of acetyl CoA, a by-product of incomplete beta-oxidation of long-chain fatty acids. => [[General medicine 5#DKA pathophysiology|Diabetic ketoacidosis]]

Other hormones regulating blood glucose level

#2021BSQ-NOV Q07

• Catecholamines increase hepatic glucose output;
• Epinephrine (adrenaline) decreases peripheral uptake of glucose.
  • provides anti-insulin action.
  • Important in type 1 diabetics because they lose the ability to secrete glucagon as well! (protects them against hypoglycaemia)
• Thyroxine: hyperthyroidism exacerbates diabetes. Thyroxine increases gut absorption of glucose and potentiate catecholamine action (which is as above)
• Glucocorticoids: Have a permissive effect on the actions of glucagon and attenuating action on insulin.
  • They are necessary for glucagon mediated gluconeogenesis during fasting.
  • Hypoglycaemic effect of insulin is much stronger (even too strong!) in the absence of glucocorticoids.
  • Both effects above cause hypoglycaemia seen in Addison's disease.
  • The diabetogenic effects are due to increase in protein catabolism, increased gluconeogenesis and decreased peripheral utilization of blucose.
• Exercise: not a hormone BUT
  • Exercise causes upregulation of GLUT-4 transported in muscle and this causes insulin independent increase in glucose uptake.

Glucose transporters

[!TIP] Mnemonic
GLUT-2 and GLUT-4 : even numbered ones are involved in insulin mediated glucose regulation.
1 and 3 are basal, non insulin dependent transporters.

Oestrogen

There are three main types of estrogen: Source

• Estrone (E1): People make this type of estrogen after menopause.
• Estradiol (E2): This is the most common type of estrogen that people make.
• Estriol (E3): This is the main type of estrogen in a pregnant person’s bloodstream. ("trimersters = 3 = estriol")

Cushing's syndrome and Cushing's disease

Features of Cushing's syndrome

1. Osteoporosis
2. Hypertension
3. Facial plethora, proximal myopathy, striae, easy bruising

Commonest cause is iatrogenic;
All glucocorticoids suppress ACTH -> ACTH, and serum cortisol will be low in iatrogenic cushing's syndrome.

The diagnosis of Cushing syndrome is established when at least two different first-line tests are unequivocally abnormal, and physiologic hypercortisolism has been excluded

Sequence of evaluation:

If a patients has feature of Chushing's syndrome

1. It has to be proved that the patient has elevated cortisol
2. The cause of elevated cortisol must be determined.

Initial testing to confirm elevated cortisol:

1. bedtime salivary cortisol

   1. There is a pre-bed time cortisol level nadir in normal physiology.
   2. This is preserved in physiologic hypercortisolism but absent in Cushing's syndrome.

2. 24 hour urinary free cortisol - Measures the total daily cortisol production without being affected by the cyclical variations in it's production.

3. Low dose DST

   1. The low-dose DSTs are standard screening tests to differentiate patients with Cushing syndrome of any cause from patients who do not have Cushing syndrome.
   2. A positive low dose DST will show impaired suppression of cortisol secretion.
   3. The high-dose DSTs are not used to make the diagnosis of Cushing syndrome. (High dose DST is used to identify the source of ACTH if it is abnormally high (i.e Cushing's disease Vs. ectopic ACTH)
   4. There are two forms of low dose DST
      1. Overnight 1mg dexamethasone suppresion test
      2. two day 2 mg DST
   5. Both will show impaired suppression of cortisol if the patient has Cushing's syndrome.

For bedtime salivary cortisol and UFC, two abnormal tests are required.

Pseudo-Cushing's syndrome

If cortisol is found to be elevated with the above preliminary tests, next step is to exclude physiologic hypercortisolism.
AKA - pseudo Cushing syndrome.

Clinically, these patients usually do not have skin or muscle manifestations of Cushing Syndrome.
Causes of pseudo-cushing syndrome (i.e causes of elevated cortisol)

1. #Pregnancy
2. Severe obesity / PCOS
3. Severe major depression
4. Poorly controlled DM
5. OSA

Because of various nuances, the above tests must be unequivocally elevated in order to diagnose Cushing's syndrome. Mild elevations are unlikely to indicate Cushing's syndrome.

Determining the cause of hypercortisolism

Once hypercortisolism has been identified and physiologic hypercortisolism as been excluded, the cause of hypercortisolism must be determined.

First step is determining if the cortisol hypersecretion is
ACTH dependent or ACTH independent.
This is done by measuring ACTH levels.

ACTH levels

Because of cyclical variations, testing at two different times is recommended.

ACTH < 5pg/ML = ACTH independent hypercortisolism

ACTH > 20pg/mL = ACTH dependent hypercortisolism.

ACTH dependent Hypercortisolism

1. The vast majority have pituitary corticotroph adenoma -(CUSHING'S DISEASE)
2. Other causes are ectopic ACTH and ectopic CRH.

Determining the cause of ACTH dependent hypercortisolism

1. CRH stimulation test - differentiates Cushing's disease from all other causes of hypercortisolism
   1. Corticotroph pituitary tumours respond to CRH (despite being tumours) -> AC
2. High dose dexamethason suppression test
   1. Corticotroph tumours are not resistant to negative FB by glucocorticoids
   2. Ectopic ACTH producing tumours have absolutely no inhibition from glucocorticoids. (with the exception of some pulmonar neuroendocrine tumours)
   3. Therefore, 8mg of Dexamethasone oral at 11PM will cause reduction in morning Serum cortisol.
3. Desmopressin stimulation test
   1. Used clinically when CRH is not available
   2. ADH stimulates ACTH release.
   3. Desmopressin is used to mimic this effect. (ADH and desmopressing have a similar action to CRH)
      1. In ACTH secreting adenoma (Cushing's disease) this response is preserved but in ectopic ACTH secreting lesions this response is absent.

Imaging

A mass > 6mm in size in the sella turcica supports a diagnosis of Cushing's disease.
10% of healthy people have masses <6mm in size.

Invasive testing

Sampling the ACTH level from the petrosal sinus can be used if the diagnosis is uncertain.

Adrenaline synthesis

[!TIP] Mnemonic
Dopamine -> Norad -> adrenaline -> ?waste products

#2021BSQ-NOV Q31

Leukemoid reaction refers to a white blood cell (WBC) count >50,000/microL from causes other than leukemia. (Usually severe reaction to an infection).

The majority of cells are mature neutrophils, but often accompanied by a prominent left shift.

[!INFO] Left shift
"Left shift" : ill defined term meaning increased band forms, myelocytes and metamyelocytes. -> indicates infection, sepsis of chronic myeloid leukemia.
Myelocytes are neutrophil precursors seen mainly in bone marrow. Metamyelocytes are their descendants, and can be seen in the blood.
Greek "meta" means 'after'.
Band forms are immature neutrophils whose nucleus hasn't yet become segmented and have a C or S shape.

Some Causes:

• Infections: Tuberculosis infection, Clostridium difficile infection, pertussis
• Asplenia / hyposplenia
• Medications: myeloid cytokines and all-trans retinoic acid.

Clues for cause or neutrophilia:

1. Toxic granules present or Dohle bodies -> Infection / inflammation
2. Left shift -> infection or Chronic myeloid leukemia.
3. Significant number of myeloid blasts -> Acute myeloid leukemia

Spurious neutrophilia / false neurophilia / pseudo neutrophilia:
interferrenace with the particle counter can case false neutrophelia in

• Platelet clumping
• Cryoglobulinaemia

Cellular adaptations

#2021BSQ-NOV Q34

Hyperplasia and hypertrophy

Important points:

• Hyperplasia occurs in cells that retain the ability to divide (eg. Smooth muscle of uterus). Hypertrophy occurs in cells that cannot divide (eg. Cardiac and Skeletal muscle)
• Both hyperplasia and hypertrophy can occur simultaneously. (eg Gravid uterus)
• Both can be physiological or pathological. (LVH in hypertension)
• Stimuli for hypertrophy can be mechanism or chemical (signalling molecules).
• If stress exceed adaptive capabilities of cell, cell injury results.
  • Hypertrophy has limits; when a particular limit of adaptive hypertrophy is reached, degenerative changes occur in the contractile unites of muscle. This is seen in decompensation of heart failure. The degenerative changes results in ventricular dilation.
• Hyperplasia: stimulated by growth factors. Can occur simulatenously with hypertrophy.
• There are two types of physiologic hyperplasia
  • Hormonal -> in response to hormones
  • Compensatory -> Remaining liver cells begin to divide after liver resection due to paracrine peptide signals.
• Pathologic hyperplasia: caused by abnormal hormone production: eg endometrial hyperplasia.
• Pathologi hyperplasia is distinguised from cancer by the preserved sensitivity of cells to external growth factors. i.e in pathologic hyperplasia, if the growth factor is removed, hyperplasia stops. (but not in cancer)

Atrophy

Causes:

• Decreased work load (cells aren't needed)
• Loss off innervation (cells think they aren't needed)
• Inadequate nutrition
• Loss of blood supply
• Aging (senile atrophy)

[!INFO] Definition of atrophy
In atrophy, a shell shrinks to a smaller size with reduced function so that it can survive under the new (less conducive) growth conditions imposed by factors listed above.
Atrophic cells are not dead.
Cellular mechanisms:

• Decreased protein synthesis
• Proteolysis - ubiquitin-proteasome pathway which may also be involved in cancer cachexia
• Increased autophagy.

Metaplasia

Reprogramming of stem cells to differentiate into a cell type that is more suitable to cope with the new stresses than the original cell type at that location.
I.e results in replacement of one type of mature cell with another type of mature cell.
It is a reversible change;
Example: Squamous metaplasia of respiratory epithelium in smokers.
Vitamin A is essential for normal epithelial differentiation.

Pathology of cancers

Anaplasia

Anaplasia: "backward formation" - loss of structural and functional differentiation of cells. A hallmark of malignancy

[!INFO] Dedifferentiation Vs. Lack of differentiation
There may be some technical difference between dedifferentiation and inability to differentiate at all (as seen in cancers of stem cells)
See Robbins (Page 165).

Pathologic features of anaplastic cells:

• Anaplastic cells show pleomorphism: variation in size and shape.
• Extremely hyperchromatic nuclei.
• Large nuclei with high nuclear to cytoplasmic ratio.
• Bizzare nuclear shapes
• Numerous and atypical mitoses.

Dysplasia

Dysplasia:

• "Anarchy or normal cellular order" ->
• Mainly seen in epithelial lesions.
• There is
  • Pleomorphism with large, hyperchromatic nuclei.
  • Loss of cellular uniformity
  • loss of cell orientation
  • Increased mitotic count with mitoses in unusual areas (i.e away from basement membrane)
• Dysplasia generally precedes malignant transformation at that site.
• However, mild to moderate dysplasia can spotaneously regress as well.
• Therefore, dysplasia is NOT synonymous with cancer.
• Dysplasia involving all layers of the epithelium is called carcinoma in situ.

Infectious causes of cancer

Oncogenic infections

==From Wikipedia==

Oncogenic viruses:

Source
There are 7 known oncogenic viruses

• 
• Cryoglubulins can cause a systemic small to medium vessel vasculitis triggered by cryoglobulin containing immune complexes.
• Type 1 - caused by cryoprecipitable monoclonal immunoglobulins.

Gatric cancer can be

• Gastrooesophageal
• Proximal
• Distal
  Distal cancer incidence as reduced greatly but proximal and GE cancer incidence has increased.

H. pylori and gastric cancer

H pylori infection is associated with several types of gastric cancer.
Treatment of H pylori infection reduces cancer risk.
The exact mechanism is not known but there are several theories.

• H pylori may increase [[2022 May Basic Sciences#Gastric cancer|Gastrin]] secretion as above.
• H pylori can cause chronic gastritis leading to metaplasia.

Types of cancer associated with H. pylori:

• Gatric adenocarcinoma (both diffuse and intestinal types)
• MALToma
  • The stomach is the commonest site of MALT tumours. (mucosa associated lymphoid tissue tumours)
  • Normal stomach doesn't have significant lymphoid tissue but H-pylori infection leads to aggregation of lymphocytes in the lamina propria.
  • Lymphocyte activation leads to follicle formation -> somehow proceeds to MALToma

(AKA TNF-alpha, AKA TNF-α, aka cachexin)

1. mitochondrial or intrinsic pathway => promoted by DNA damange and accumulation of misfolded proteins. Pro apoptotic proteins leak out of the mitrochondria; This pathway is inhibited when the cell receives growth signals.

Endothelial cell contraction occurs rapidly after binding of histamine, bradykinin, leukotrienes, and many other mediators to specific receptors, and is usually short-lived (15 to 30 minutes). A slower and more prolonged retraction of endothelial cells, resulting from changes in the cytoskeleton, may be induced by cytokines such as tumor necrosis factor (TNF) and interleukin-1 (IL-1).

1. TNF
   TNF and IL-1 : the main role of TNF and IL-1 is in endothelial cell activation which causes increased vascular permeability and increased expression of adhesion molecules to facilitate phagocyte (neutrohil) migration and to enhance production of chemokines and other cytokines.

Hürthle cell carcinoma is a rare, more agrressive variant of follicular carcinoma. 5 year survival is 50 - 60%.

[!INFO] Hurthle cells are seen in non malignant conditions as well
Hurthle cells are clasically seen in

• Hashimoto thyroiditis
• multinodular hypoplasia
• lymphocytic thyroidis
• Source

[!TIP] Watery diarrhoea

#2021BSQ-NOV Q33

• Molecules whose concentration Incr. or Decr. by 25% during inflammation.
• Plasma levels are mainly controlled by rate of hepatic production.
• Hepatic production is regulated by cytokines - IL-6, IL-1 beta, TNF-alpha and interferron Gamma secreted by macrophages during inflammation.

"For F*cks Sake, Protect Harry's Ass Hole " - +ve acute phase reactancts.